Lithium (Li), an established treatment for bipolar disorders, is emerging as a potential neuroprotective therapy for acute and chronic neurodegenerative diseases. However, a significant side effect of Li therapy is nephrogenic diabetes insipidus (NDI). Li-induced NDI has been attributed to increased production of prostaglandin E2 (PGE2) by the medullary collecting duct (mCD). Current therapies aimed at direct inhibition of PGE2 synthesis in Li-induced NDI are encountered with serious side effects, including Li intoxication. Replacement of the current side effect-prone drugs with new ones based on improved understanding of molecular pathophysiology of Li-induced NDI should result in improved efficacy and fewer side effects in the clinic. In this context, we discovered that increased production of renal PGE2 in Li-induced NDI may be related to the hypersensitivity of P2Y2 receptor, an extracellular nucleotide (ATP/UTP) receptor, in the medullary collecting duct (mCD). Preliminary studies conducted in rat model showed that administration of apyrase (soluble ecto-nucleotidase) causes significant reduction in Li-induced polyuria, associated with normalization of the augmented release of P2Y2 receptor agonist-stimulated PGE2 release by the mCD. We also found that genetic deletion of P2Y2 receptor results in marked resistance to the development of Li-induced polyuria. Based on these findings, the central hypothesis of this proposal is that hypersensitivity and enhanced signaling through P2Y2 receptor plays a significant role in vivo in the development of Li-induced NDI by markedly increasing the production of PGE2 by the mCD. We further propose that therapeutic scavenging of the extracellular nucleotides by native and engineered ecto-nucleotidases should offer an efficacious and safer approach for the treatment of Li-induced NDI. The specific aims are: (i) to determine whether constitutive scavenging of extracellular nucleotides blunts the development of Li-induced NDI. To achieve this goal, we will use CD39 (NTPDase1, an ecto-nucleotidase) over expressing transgenic mouse model;and (ii) to determine whether pharmacological scavenging of extracellular nucleotides by the administration of native or engineered soluble NTPDases will ameliorate the Li-induced polyuria in rats. The long-term objective of this proposal is to develop innovative therapies for Li-induced NDI based on the approach of specific blockade of the activity of P2Y2 receptor by scavenging the extracellular nucleotides. PUBLIC HEALTH RELEVANCE: Lithium is an effective drug for the treatment of bipolar disorders, which affect about 2-3% of general population and 4-6% of Veterans. In addition to its long-standing use for the treatment of bipolar disorders, in recent years lithium has been identified as a potent drug for the treatment of acute and chronic neurodegenerative disorders, such as stroke or Alzheimer's, respectively. However, the use of lithium is associated with adverse side effect on the kidney - induction of diabetes insipidus or water diabetes. Current therapies for the treatment of diabetes insipidus are encountered with serious side effects, including lithium intoxication. This project, which identifies novel molecular pathways that may be responsible for the excessive loss of water and salt, proposes to further investigate these pathways with a possibility to develop innovative therapies for use in the clinic.